It is widely believed that the greatest achievement that can be made in cancer management is the early detection and subsequent treatment of disease. The next generation cancer management strategies will greatly benefit from technologies that combine imaging, targeting, and treating of the earliest stage disease. Recent advances in nanotechnologies have produced a class of optically active metal particles with highly desirable molecular and optical properties suitable for combining these three aspects. They can be imaged optically as they exhibit strong optical absorption that is tunable to the near infrared spectrum where in vivo optical imaging is optimum. As they are fabricated from noble metals, they are biologically non-reactive and non- toxic, and they have surface chemistries that are conducive to antibody labeling. Their metal structure is extremely stable and efficiently converts absorbed light to heat, allowing for photothermal therapeutic applications. Successful translation of these nanoparticles as combined imaging, targeting, and therapeutic agents requires the development of non-invasive imaging strategies, in vivo cell specific targeting protocols, and optimum dosimetry planning. The proposed project represents a long term interdisciplinary effort to develop a technology combining imaging, targeting, and treatment of cancer using metal nanoparticles as the mediator. The proposed studies will develop minimally invasive optical imaging and sensing tools for quantitative assessment of nanoparticle location, tissue pathology, and therapeutic response (Aim 1). We will investigate the kinetics of nanoparticle tumor targeting and develop strategies for efficient delivery nanoparticles to the tumor site (Aim 2). We will determine the optimum laser irradiation of the nanoparticle labeled tumor to induce cell injury at the single cell level. Our approach includes multiscale molecular modeling of protein-nanoparticle interactions and in vitro verification (Aim 3). The final outcome of this project will demonstrate in a preclinical animal model highly selective cancer cell killing without damaging immediately adjacent normal cells (Aim 4). In the long term, such technologies offer the possibility to circumvent current limitations of surgical removal by selectively treating disease at the cellular and sub-cellular level. It is widely believed that the greatest achievement that can be made in cancer management is the early detection and subsequent treatment of disease. The proposed project represents an interdisciplinary effort to develop a technology combining imaging, targeting, and treatment of cancer using metal nanoparticles as the mediator. In the long term, such technologies offer the possibility to circumvent current limitations of surgical removal by selectively treating disease at the cellular and sub-cellular level.